Pharmaceutical preparations with which the drug concentration in blood can be maintained at a desired level for a prolonged period of time are very useful since the frequency of administration thereof can be reduced and the compliance can be improved. Such control of blood concentration can serve to avoid unnecessary increases in blood concentration and thereby reduce or alleviate adverse effects of the drug. Therefore, such pharmaceutical preparations are useful as compared with ordinary preparations.
Various dosage forms have been proposed as means of controlling the drug concentration in blood. For instance, there may be mentioned 1 a preparation which comprises a core consisting of drug-containing granules and a semipermeable coat film covering said core, so that the drug can be released therefrom gradually in a body fluid for prolongation of the drug action, 2 gel matrix tablets that are made by admixing a water-soluble polymer having good gel forming ability with a drug and other appropriate ingredients and tableting the mixture for attaining sustained release by making use of the phenomenon of dissolution and peeling of the gel and 3 wax matrix tablets made by admixing a basically water-incompatible animal or vegetable oil or wax with a drug and tableting the mixture for attaining sustained release, among others.
However, the dosage forms mentioned above are invariably wanting in the function to control the transfer from the stomach to the small intestine after taking thereof and, as a result, cannot display satisfactory sustained release characteristics in many instances.
One of the means for solving this problem is to cause the pharmaceutical preparation to adhere to the gastrointestinal tract wall.
For instance, mention may be made of the method comprising coating pellets with an adhesive material (Japanese Kokai Tokkyo Koho JP 63-101332).
This technology comprises coating relatively large granular cores with an adhesive material to attain a sustained action. In this method, it is important that the adhesive material be used in large amounts to secure sustained release for a prolonged period of time.
However, to cover cores with a large amount of a highly sticky material is accompanied by problems very difficult to solve from the technology and cost viewpoints, for example measures for coping with secondary particles during handling and processing, and lowering the viscosity of the coating solution, which causes increases in process hours, for instance. In addition, since the adhesion time depends on the mutual relation between the adhesive power and detaching force (peeling force), such large grain size pellets show an adhesion time shortened due to the own weight of each grain as compared with fine particles.
Therefore, this technique is not always appropriate as a means of attaining sustained release by ensuring a long period of adhesion.
With another dosage form having adhesiveness, the transfer of a pharmaceutical preparation in the gastrointestinal tract is forcedly controlled by utilizing a carrier comprising a combination of an oil and a water-soluble polymer (Japanese Kokai Tokkyo Koho JP 61-233632).
Supposedly, this technique can prolong the adhesion time as compared with the method mentioned above because fine particles of a water-soluble polymer can be mixed in an oil.
However, it is evident that mere mixing of an oil with a water-soluble polymer does not necessarily give an excellent sustained release preparation. The reasons are as follows.
1 When, for example, the affinity between the oil and water-soluble polymer is strong, the water-soluble polymer may be dissolved in the oil as the case may be. In that case, no adhesiveness is exhibited any longer. PA1 2 When the oil component is a liquid oil, the dosage form most preferred from the overall viewpoint, including administrability and economic aspects, will be a capsule form. PA1 3 Furthermore, a polydiorganosiloxane is selected as the oil component in Japanese Kokai Tokkyo Koho JP 02-258718. However, said substance is physiologically active in that it can eliminate the gas in the gastrointestinal tract at a dose of about 120 mg per day. Naturally, it is not desirable to use such an oil component as an additive to pharmaceutical preparations.
However, all oils are not utilizable in such a dosage form. For instance, propyleneglycol, glycerol, polyethylene glycol and the like, which are given as examples of the oil component in Japanese Kokai Tokkyo Koho JP 61-233632, when filled into hard capsules, will cause swelling, deformation or dissolution, for instance, of the capsule shell irrespective of the water-soluble polymer used combinedly.
Therefore, it is difficult to use such oil components as mentioned above in preparing carriers for sustained release for making encapsulated pharmaceutical preparations.
On the other hand, the most serious problem raised by capsules filled with a dispersion composed of an oil and a water-soluble polymer is that when allowed to stand in an environment where the ambient air has a humidity of about 75%, the capsule contents tend to cake. A conceivable measure therefor may be strict moistureproof packaging for blocking the influence of moisture from outside. Even when such measure is taken, the phenomenon of caking still takes place. Thus, the contents, whether packed or not, will harden. This is a phenomenon specific to this dispersed system and is a physicochemical phenomenon not readily predictable in the current technology.
The caking phenomenon mentioned above involves not only physical changes of the contents but also loss of the adhesiveness of the carrier observable immediately after preparation thereof and, further, a rapid reduction in bioavailability, rendering the pharmaceutical preparation quite meaningless.